Cianciaruso Chiara, Phelps Edward A, Pasquier Miriella, Hamelin Romain, Demurtas Davide, Alibashe Ahmed Mohamed, Piemonti Lorenzo, Hirosue Sachiko, Swartz Melody A, De Palma Michele, Hubbell Jeffrey A, Baekkeskov Steinunn
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Diabetes. 2017 Feb;66(2):460-473. doi: 10.2337/db16-0671. Epub 2016 Nov 21.
The target autoantigens in several organ-specific autoimmune diseases, including type 1 diabetes (T1D), are intracellular membrane proteins, whose initial encounter with the immune system is poorly understood. Here we propose a new model for how these proteins can initiate autoimmunity. We found that rat and human pancreatic islets release the intracellular β-cell autoantigens in human T1D, GAD65, IA-2, and proinsulin in exosomes, which are taken up by and activate dendritic cells. Accordingly, the anchoring of GAD65 to exosome-mimetic liposomes strongly boosted antigen presentation and T-cell activation in the context of the human T1D susceptibility haplotype HLA-DR4. Cytokine-induced endoplasmic reticulum stress enhanced exosome secretion by β-cells; induced exosomal release of the immunostimulatory chaperones calreticulin, Gp96, and ORP150; and increased exosomal stimulation of antigen-presenting cells. We propose that stress-induced exosomal release of intracellular autoantigens and immunostimulatory chaperones may play a role in the initiation of autoimmune responses in T1D.
包括1型糖尿病（T1D）在内的几种器官特异性自身免疫性疾病中的靶自身抗原是细胞内膜蛋白，目前人们对它们与免疫系统的初次接触了解甚少。在此，我们提出了一个关于这些蛋白如何引发自身免疫的新模型。我们发现，大鼠和人类胰岛会将人类T1D中的细胞内β细胞自身抗原、GAD65、IA-2和胰岛素原释放到外泌体中，这些外泌体会被树突状细胞摄取并激活。相应地，在人类T1D易感单倍型HLA-DR4的背景下，将GAD65锚定到外泌体模拟脂质体上可显著增强抗原呈递和T细胞激活。细胞因子诱导的内质网应激增强了β细胞的外泌体分泌；诱导了免疫刺激伴侣蛋白钙网蛋白、Gp96和ORP150的外泌体释放；并增加了外泌体对抗抗原呈递细胞的刺激。我们提出，应激诱导的细胞内自身抗原和免疫刺激伴侣蛋白的外泌体释放可能在T1D自身免疫反应的启动中起作用。
